FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev 14th World Congress on Gastrointestinal Cancer San Francisco, CA January 24-26 2013 FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev as 1st-line treatment of metastatic colorectal cancer: results of the phase III randomized TRIBE trial Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Trenta P, Tomasello G, Ronzoni M, Ciuffreda L, Zaniboni A, Tonini G, Buonadonna A, Valsuani C, Chiara S, Carlomagno C, Boni C, Marcucci L, Boni L, Falcone A on behalf of the GONO Investigators Slides based on TRIBE report v1.3 Jan 16 2013

Disclosures Bayer, Consultant

Background Doublets plus bev are a standard of care in the first-line treatment of mCRC Hurwitz et al. NEJM ‘04, Saltz et al. JCO ‘08 FOLFOXIRI demonstrated superior RR, PFS and OS compared to FOLFIRI in a previous phase III trial by the GONO group Falcone et al. JCO ‘07 FOLFOXIRI vs FOLFIRI RR: 66 vs 41 PFS 9.8 vs 6.9 OS 22.6 vs 16.7 FOLFOXIRI plus bev achieved promising results (median PFS 13.1 mos, RR 77%), with a safe toxicity profile in a phase II study (N=57) Masi et al. Lancet Oncol ‘11

Objective To confirm the superiority in the 1st- line treatment of unresectable mCRC of FOLFOXIRI triplet compared to FOLFIRI doublet also when bevacizumab is associated to chemotherapy

FOLFIRI + bev* FOLFOXIRI + bev* Study Design FOLFIRI + bev* Bev 5 mg/kg ev g1 Irinotecan 180 mg/sqm ev g1 L-LED 200 mg/sqm ev g1 5-FU 400 mg/sqm ev g1 bolus 5-FU 2400 mg/sqm ev gg13 1st line unresectable mCRC pts stratified by center PS 0/1-2 adjuvant CT R 1:1 FOLFOXIRI + bev* Bev 5 mg/kg ev g1 Irinotecan 165 mg/sqm ev g1 Oxaliplatin 85 mg/sqm ev g1 L-LED 200 mg/sqm ev g1 5-FU 3200 mg/sqm ev gg13 *both repeated every 2 wks for a max of 12 cycles followed by maintenance with 5FU/bev until PD

Experimental ARM : FOLFOXIRI + bev Treatment schedule Experimental ARM : FOLFOXIRI + bev bev 5 mg/Kg irinotecan 165 mg/sqm oxaliplatin 85 mg/sqm L-LV 200 mg/sqm 5FU flat continuous infusion 3200 mg/sqm 48h 30 min 1 hour 2 hours 48 hours

Endpoints Primary end-point Progression free survival Secondary end-points Response Rate Secondary R0-resection rate Overall survival Safety profile Biomarkers evaluation

(approximately 450-500 patients to be randomized) Statistical considerations Assuming a median PFS for FOLFIRI plus bev of 11 months (Kozloff et al. JCO ’09, Sobrero et al. Oncology ‘09) to detect a HR for PFS of 0.75 in favour of FOLFOXIRI plus bev with a 2-sided type 1 error: 0.05; power: 80% AVIRI median PFS: 11.1 ARIES median PFS: 10.2 BRiTE median PFS: 10.8 379 events required (approximately 450-500 patients to be randomized)

Key Eligibility Criteria Histologically proven adenocarcinoma Unresectable mCRC not previously treated for metastatic disease At least one measurable lesion according to RECIST 1.0 Age 18-75 ECOG PS ≤ 2 (ECOG PS = 0 if age = 71-75 years) Adjuvant oxa-containing chemotherapy allowed if more than 12 months elapsed between the end of adjuvant and first relapse Adequate bone marrow, liver and renal functions

Patients’ demographics – ITT population Characteristic, % patients FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 Sex (M / F) 61 / 39 60 / 40 Median Age (range) 60 (29 – 75) 61 (29 – 75) ECOG PS (0 / 1-2) 89 / 11 90 / 10

Baseline disease characteristics – ITT population Characteristic, % patients FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 Synchronous Metastases (Y / N) 81 / 19 79 / 21 Prior Adjuvant CT (Y / N) 12 / 88 Primary Tumor Site (right / left / NE) 24 / 70 / 6 35 / 60 / 5 Number Metastatic Sites (1 / >1) 24 / 76 31 / 69 Liver Only Disease (Y / N) 18 / 82 23 / 77 Resected Primary (Y / N) 65 / 35 69 / 31 Kohne score (low / interm / high / NE) 41 / 44 / 11 / 4 43 / 44 / 7 / 6

Primary endpoint: PFS – ITT population FOLFIRI + bev FOLFOXIRI + bev Median follow up: 26.6 mos FOLFIRI + bev: N = 256 / Progressed = 225 FOLFOXIRI + bev: N = 252 / Progressed = 199 FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.2 mos Unstratified HR: 0.73 [0.60-0.88] p=0.0012 Stratified HR: 0.71 [0.59-0.86] p=0.0006 Progression-free survival probability PD-free rate at 2 years: 11.4% vs 20.3% F-up time (months) FOLFIRI/bev 256 198 93 42 22 10 3 FOLFOXIRI/bev 252 203 125 64 27 15 8 1

Subgroup analyses of PFS 0.5 1 1.5 2 Experimental better Control Better

Secondary endpoint: Response rate (ITT population) Best Response, % FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 p Complete Response 3% 4% Partial Response 50% 61% Response Rate 53% 65% 0.006 Stable Disease 32% 24% Progressive Disease 5% 2% Not Assessed 10% 9% Vd ppgg 163-164 del report

Target lesions shrinkage: waterfall plots FOLFIRI + BEV FOLFOXIRI + BEV

Overall Safety – Safety population Patients, % FOLFIRI + bev N = 254 FOLFOXIRI + bev N = 250 Serious AEs 19.7% 20.4% Fatal AEs 3.5% 2.8% Treatment-related deaths 1.6% 2.4% Early deaths (within 60 days from random) 2.7% 3.6%

Toxicity Profile – Safety population G3/4 adverse events, % patients FOLFIRI + bev N=254 FOLFOXIRI + bev N=250 p Nausea 3 1.000 Vomiting 4 0.492 Diarrhea 11 19 0.012 Stomatitis 9 0.048 Neutropenia 20 50 <0.001 Febrile neutropenia 6 0.315 Neurotoxicity 5 Hypertension 2 0.157 Venous Thrombosis 7 0.593 Arterial Thrombosis 1 Bleeding

Treatment duration and management FOLFIRI + bev N = 254 FOLFOXIRI + bev N = 250 Induction CT cycles, median (range) 12 (1-25) 11 (1-21) Delayed cycles 6% 16% Cycles with dose reduction 8% 21% 5-FU relative dose intensity 83% 73% Irinotecan relative dose intensity 84% 74% Oxaliplatin relative dose intensity NA 75%

Summary FOLFOXIRI plus bev compared to FOLFIRI plus bev: significantly reduced the risk of progression (HR=0.73, p=0.0012) and PFS benefit was consistent among all analyzed subgroups significantly increased response rate (65% vs 53%, p=0.005) increased the incidence of grade 3-4 diarrhea, stomatitis and neutropenia, but not of febrile neutropenia, serious adverse events and treatment related deaths

Conclusions The trial achieved its objective of confirming the superiority of FOLFOXIRI vs FOLFIRI in terms of PFS, also in combination with bev FOLFOXIRI plus bev compared to FOLFIRI plus bev moderately increases specific side effects but the overall safety profile is acceptable Based on these results FOLFOXIRI plus bev represents a new option for the treatment of mCRC patients selected according to the eligibility criteria of this study Secondary resections, post-progression treatments and overall survival analyses are ongoing (follow-up still immature) Translational biomarker analyses are ongoing

REGGIO EMILIA: Boni ROMA GEMELLI: Barone ROMA UMBERTO I: Cortesi Acknowledgements PATIENTS INVESTIGATORS and THEIR 33 CENTERS all over Italy ANCONA: Cascinu AOSTA: Numico AREZZO: Bracarda AVIANO: Frustaci BRESCIA: Zaniboni CALTANISSETTA: Vitello CREMONA: Passalacqua CUNEO: Merlano FIRENZE: Ribecco GENOVA IST: Chiara GENOVA GALLIERA: De Censi LECCE: Lorusso LEGNAGO: Bonetti LIVORNO: Cappuzzo LUCCA: Baldini MILANO NIGUARDA: Siena MILANO HSR: Villa MIRANO: Vinante MONZA: Bidoli NAPOLI: Tortora PARMA: Ardizzoni PADOVA: Zagonel PISA: Falcone, Ricci PIOMBINO: Dargenio PONTEDERA: Allegrini PRATO: Di Leo REGGIO EMILIA: Boni ROMA GEMELLI: Barone ROMA UMBERTO I: Cortesi ROMA Campus Biomedico: Tonini SONDRIO: Bertolini TORINO: Ciuffreda VERSILIA: Amoroso Roche Special thanks go to: Dr. CREMOLINI Chiara, Dr. BONI Luca, Dr. MASI Gianluca